The principal investigator (P.I.) for this award application has previously been productive in developing research and clinical applications for myocardial contrast echocardiography (MCE). This past research provided the P.I. with a basic understanding of ultrasound physics, coronary physiology and perfusion imaging. MCE uses microbubbles as a contrast agent during simultaneous ultrasound imaging, and has recently developed into a unique tool for the quantification of myocardial blood flow (MBF) and myocardial blood volume (MBV). Using both intracoronary injections, and continuous intravenous infusions of micro-bubbles, MCE also has the ability to discriminate between extramyocardial and capillary sites of MBF control. An improvement in our understanding of the adaptive microcirculatory changes associated with coronary artery disease (CAD) could potentially allow earlier identification of patients with this disease. The specific aims in this proposal are therefore to assess adaptive changes in MBV, the transmural distribution of MBF, and phasic changes in MBF in the setting of CAD. Acute and chronic animal models that simulate CAD in humans, and patients undergoing coronary angiography, will be used to evaluate microvascular sites of autoregulation in the setting of CAD. In the presence of exogenous hyperemia, capillaries may collapse in the bed distal to the stenosis. The physiologic basis for this occurrence, and the basis for stenosis detection using non-invasive perfusion imaging will be assessed. The transmural distribution of flow is inhomogeneous, and is related to differences in intramyocardial pressure and oxygen demands in different myocardial layers. Determining the endocardial/epicardial distribution of MBF and MBV could provide an unique way to both detect and quantify stenosis seventy. Similarly, phasic changes in coronary blood flow are influenced by myocardial function, coronary perfusion pressure, and the state of the microcirculation. Studies using MCE to evaluate phasic flow patterns in the setting of CAD, both at rest and during exogenous pharmacologic stimulation will be performed. The ultimate goal of this research is to gain a better understanding of the coronary microcirculation that will allow improved non-invasive diagnosis of CAD. The protocols outlined above require a comprehensive understanding of myocardial microcirculatory physiology, microvascular perfusion, mathematical modeling and ultrasound physics, for which Sanjiv Kaul, M.D. will serve as mentor. Furthermore, if the hypotheses of the current proposal are correct, MCE will offer novel insights into microvascular physiology that are currently not attainable with other non-invasive imaging methods, and will provide new diagnostic modalities for Cardiology.